The invention pertains to compounds having antimicrotuble activity which are taxoid-based derivatives and demonstrate prolonged anti-neoplastic activity and/or improved water solubility. More particularly, the invention is directed to taxol derivatives which are substituted in the 7-position with a substituted hydrazide or carbazate.
Taxol, or paclitaxel has been investigated as an anti-cancer agent. It is a plant product derived in minute quantities from the needles and bark of the western pacific yew, Taxus brevifolia. The pacific yew is a rare, slow-growing tree which is not typically cultivated. Taxol is a potent inhibitor of cell replication. It is known as an antimicrotuble agent and is believed to inhibit cell mitosis through the enhancement of the rate of microtubular assembly in vitro. This induced aggregation of microtubules is irreversible and microtubular depolymerization is effectively prevented. Numerous studies indicate that the agent has potent cytotoxic activity against a range of human malignancies including breast cancer, metastatic melanomas and ovarian carcinomas. It has also demonstrated antileukemic and tumor inhibitory properties. It is furthermore known that combinations of taxol and radiation therapy have more than an additive interaction effect in inhibiting cell mitosis. Unfortunately the general use of taxol in anticancer therapy has been severely limited by short supply, poor water solubility and immunogenicity. In addition, the anti-neoplastic portions of the western pacific yew tree are very minute and extraction of these portions is complicated and costly. One solution to the problem of short supply has been suggested in U.S. Pat. No. 5,019,504 which discloses an artificial media for producing certain desirable alkaloids. Alternatively, synthetic derivations such as taxotere and taxol intermediates have also been reported, for example, in U.S. Pat. No. 5,015,744.
Hypersensitivity reactions from taxol administration are also known. These include gastrointestinal toxicity and abdominal pain. See J. Clin. Oncol. 8:1263-1268 (1990). Since taxoids are usually extracted from a natural plant source, some hypersensitivity is expected. However, certain non-aqueous vehicles which have been used to overcome the water solubility problems of taxol have also been implicated in causing these hypersensitivity reactions. Therefore, although taxoids hold promise as therapeutic agents, there is a need to provide taxoid-based derivatives which are more water soluble and/or are more active against a wider range of virulent neoplasms than taxol. The present invention provides such a water soluble form of taxol.